Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Abstract

IntroductionThe von Willebrand factor (VWF) is an essential component of hemostasis at sites of vascular injury. This hemostatically active adhesion ligand also plays a critical role in thrombus formation at the site of a ruptured atherosclerotic plaque and in platelet aggregation induced by high fluid shear stress in areas of severe vascular stenosis. The former results in myocardial infarction when it occurs in coronary arteries, whereas the latter is a major cause of thromboembolism associated with ischemic stroke. 1 VWF is the largest multimeric glycoprotein in the plasma. It is exclusively synthesized in endothelial cells and megakaryocytes initially as a monomeric glycoprotein. In the endoplasmic reticulum and Golgi apparatus of these cells, the monomers form C-terminal disulfide-linked dimers. A various number of dimers subsequently form multimers through N-terminal disulfide linkages, a process assisted by the proteolytic release of a 714-amino acid propeptide. 2,3 The newly synthesized VWF multimers are either constitutively released into the circulation or stored in the Weibel-Palade bodies of endothelial cells and ␣-granules of megakaryocytes/platelets. 4,5 On stimulation, these granules secrete the stored VWF multimers that are rich in ultra-large and hemostatically hyperactive forms. 4,6 Ultra-large VWF multimers are also secreted under endothelial stress caused by inflammation but are rapidly and partially cleaved by the zinc metalloprotease AD-AMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) into smaller, variable-sized multimers. 7-9 The hemostatic activity of VWF multimers is determined not only by multimer size, 4,10 but also by the quantity of VWF antigen in the circulation. The plasma level of VWF multimers is determined by a dynamic balance between the rate of production and that of clearance. Although acquired conditions are known to affect synthesis and secretion, 11 genetic factors play a major role in regulating VWF synthesis and clearance. It has been reported that genetic factors are responsible for up to 66% of variation in plasma VWF antigen level, of which 30% is related to ABO blood type. 12,13 The human VWF gene is located on chromosome 12. 14,15 It spans approximately 180 kb of nucleotides and contains 52 exons that encode a multidomain prepolypeptide of 2791 amino acids. [14][15][16] The VWF gene is highly polymorphic. 17 Single nucleotide polymorphisms (SNPs) of the coding and promoter sequences in the VWF gene have been extensively studied and found to influence the levels of VWF in the circulation. Furthermore, as a heavily glycosylated polypeptide, 16,18 the level of circulating VWF is also affected by the structure of its carbohydrate side chains, which are associated with ABO blood group, primarily because of the presence or absence of a functional glycosyltransferase that adds either a N-acetylgalactosamine or a D-galactose to a D-galactose side chain on the H antigen. 19 This structural variation in glycosylation has been reported to directly...

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

“…However, there is now an increasing recognition that intronic variants can contribute by, for example, influencing the form and efficacy of gene splicing and mRNA stability. 37 Another possibility is that SNPs in the intronic regions are in high LD with functional SNPs in adjacent regions.…”

“…It has been well established that common genetic polymorphisms in the VWF gene contribute to the variability in VWF:Ag levels. [35][36][37] The most significant SNP that marked the VWF locus was rs216303:T4C, which is located within an intronic region. Until recently, intronic polymorphisms were often considered less relevant for disease development and regulating protein levels in plasma.…”

Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study

“…We also used the fastPHASE 1.2 program to resolve haplotypes from the unphased SNP genotype data and Haploview to determine regions in strong linkage disequilibrium (LD), their cosegregation rates, and underlying haplotypes in each region. 26,29 Because of known associations between O blood type and plasma VWF levels and FVIII activity, blood type O was genotyped based on a single base deletion (G) at nt 261 (RS8176719) that shifts the reading frame to generate a premature termination codon. The truncated enzyme is unable to transfer a sugar moiety to the H Ag.…”

“…In this study, we correlated 19 FVIII SNPs with FVIII activity measured in plasma samples from 10 434 healthy American subjects of European (EA, 8056) or African descent (AA, 2378) in the Atherosclerosis Risk in Communities (ARIC) Study. In addition, 75 VWF SNPs that we have previously studied for their impact on VWF Ag 26 were also analyzed for their effect on FVIII activity.…”

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

“…Chosen based on data from Atherosclerosis Risk in Communities (ARIC) study (European ancestry) (Campos et al 2011, Smith et al 2010 and data on expression in cardiovascular disease (van Schie et al 2011). …”